Mutants

by Armand Marie Leroi

  BENEATH THE NAKED APE

  Four centuries and two continents apart, Petrus Gonsalvus and Shwe-Maong are startlingly alike. Were Petrus to discard his richly sombre robes with their scarlet facings and knot a lungyi about his waist, the two men could be brothers. Nineteenth-century scientists such as Carl von Siebold and Alexander Brandt were, however, more impressed by the resemblance of the hairy men to orangutans. Influenced by the new Darwinismus they suggested that hairiness was atavistic. This may seem like a version, albeit dressed up in scientific terminology, of the ancient equation between hairiness and bestiality. But the scientists were careful to note that though their subjects may have looked like apes, they were in fact quite human.

  One can still, occasionally, come across claims that surplus-hair mutations reveal the fur beneath the naked ape. But there is reason to think that the atavism hypothesis is wrong – at least as applied to these two families. Both the hairy Burmese and Canary Islanders are described as having exceptionally fine, silken hair. This does not really resemble the robust pelt that covers adult apes – nor even human scalp or pubic hair. And hairy as great apes are, they are less so than the hairiest humans. Petrus and Shwe-Maong had noses, cheeks and ears that were covered in hair – exactly where great apes have rather little.

  Where, then, does the surplus hair come from? One possible source is the foetus. Around five months after conception every human foetus grows a dense coat of hair. This ‘lanugo’ hair is fine, silky, less than a centimetre long, and enigmatically fleeting. Just weeks after it has grown it is shed again. Were it not for the occasional child born with lingering remnants of lanugo (often on the ears), we would hardly know that it was ever there. It seems likely that the mutation that afflicted the hairy families caused this lanugo to be retained. Instead of switching over to the normal pattern of juvenile, and then adult, hair production, their hair follicles were arrested in foetal mode.

  And not just their hair follicles. In his description of Shwe-Maong, John Crawfurd notes that the hairy Burmese man had only nine teeth: four incisors and one canine in the upper jaw, four incisors in the lower, and no molars in either. Shwe-Maong’s daughter, Maphoon, had even fewer. Careful inquiries showed that they had not lost their missing teeth: they had never grown them. It was as if their teeth and hair had simply come to a halt somewhere around the sixth month of foetal development even as the rest of their bodies marched on.

  Darwin himself knew of the Burmese hairy family. In The descent of man and selection in relation to sex (1859) he cites the bribe needed to secure Maphoon a husband as proof that hairiness in women is universally unattractive. Nowhere, however, does he suggest that hairiness is an atavism. He is, instead, interested in the connection between hair and teeth. A Mr Wedderburn had told him of a ‘Hindoo’ family in the Scinde – modern-day Pakistan – in which ten men from four generations were almost entirely toothless, but, far from being hairy, were rather bald – and had been so from birth. The bald, toothless Hindoos also lacked sweat glands; unable to perspire, they wilted in Hyderabad’s heat.

  Hair, teeth, sweat glands and (though Darwin does not mention them) breasts, organs seemingly so various in their purpose and plan, are intimately connected. They are all places where skin has swollen or cavitated to make something new. The simple tube that is a hair follicle, the robust anvil of dentine and enamel that is a tooth, and the bulging burden of ducts that is a breast, are all variations on a constructional theme. A genetic disorder – there are more than a hundred – that affects one of these organs will often affect another.

  These organs do not merely share an origin in skin; they are also made in much the same way. Even as hair follicles are forming throughout the foetal epidermis, other epidermal cells are clumping and cavitating to form teeth or mammary glands. Like the hair follicle, each of these skin organs is a chimera: part ectoderm, part mesoderm.

  The kinship between all these organs can be seen in the molecular signals that make them. The ‘Hindoos’ still live near Hyderabad, where, confusingly, they are known as ‘Bhudas’ but are in fact Muslim. By 1934, six generations of Bhudas had spread across eight families. Now there are many more. Their distinctive appearance means that they recognise each other as relations, but the name of their mutant forebear seems to be forgotten. Just as Darwin’s correspondent said, they have neither sweat glands nor teeth (except for the occasional molar), but they do have at least a little scalp hair. They carry a mutation in a gene that encodes a protein called ectodysplasin, named for the disorder its absence causes: Ectodermal dysplasia. A mutation in the same gene may also explain the Mexican hairless dog. Alias El perro pelon or the Xoloitzcuintle, the dog is said to have been bred by Aztecs in the fourteenth century, possibly for meat but more likely as a kind of bed-warmer. It, too, is bald, toothless and has dry and crinkly skin for want of sebaceous glands.

  An even deeper organ-kinship is evident in an odd variety of aquarium fish. Since at least the start of the Tokugawa Shogunate in the early seventeenth century, Japanese fanciers have bred the Medaka, Oryzias latipes, a small fish that normally lives in rice-paddies. A sort of poor man’s Koi, they can be bought from the night-stalls in Japanese cities where, among the varieties for sale – albino, spotted, long-fin – there are mutants that have no scales. The Medaka’s nudity, like the Bhudas’, is caused by a mutation that disables ectodysplasin signalling.

  The use of a single molecule in the making of human teeth, hair follicles and sweat glands is a legacy of the evolutionary history that these organs share. This history is evidently also shared – at various removes – with the feathers of birds and the scales of fish and reptiles. All these organs have evolved from some simple skin organ possessed by some ancient, long-extinct ancestor of the vertebrates. No one knows exactly what this organ was. The best guess is that it resembled the tooth-like scales that give shark skin its roughness.

  The right signal can even bring about the unexpected resurrection of organs long buried by evolution. Birds don’t have teeth, but their dinosaur ancestors certainly did. If a piece of ectoderm from a foetal chicken’s beak is grafted onto a piece of mesoderm from a foetal mouse’s mandible, and both are placed in the eye-orbit of a young mouse, the chicken tissue, which has not seen a tooth for sixty million years, suddenly begins to make them: hen’s teeth, shaped something like tiny molars, complete with dentine and enamel. This implies that the molecular signals used by Tyrannosaurus rex to make its mighty fangs are the same that a mouse uses to make its miniature molars. Signals that chickens just seem to have lost.

  * * *

  Perhaps it is also the retrieval of an ancient signalling system, partly buried by evolution, that causes some people to have extra nipples or even breasts. Humans and great apes have only two nipples but most mammals have many more. Sometimes extra nipples are little more than a small dark bump somewhere on the abdomen; at other times they are fully developed breasts. They are common: between 2 and 10 per cent of the population have at least one. In Europeans extra nipples or breasts are usually found somewhere below the normal ones, often in a line running directly down the abdomen. Japanese women, curiously, seem to get them above the normal breasts, often in the armpits.

  SUPERNUMERARY BREAST ON THIGH.

  These patterns of extra nipples may recollect an ancient ‘milk line’ – a row of ten pairs of teats that ran from the armpits to the thighs in some ancestral mammal. Armpit breasts are found in the lemur, Gaelopithecus volans, and the record number of nipples found on a single person seems to be nine (five on one side, four on the other). Wherever they are, extra breasts often work like normal ones, swelling and even lactating during pregnancy, and there are even accounts of women suckling children from supernumerary thigh-breasts. Extra nipples and breasts run in families, though the mutation (or mutations) that causes them has not been identified. However, a group of London researchers are attempting to determine the mutation behind a strain of mice that have eight nipples instead of the usual six
. They have already dubbed the gene Scaramanga – for the villain of the James Bond film The Man with the Golden Gun who had, as a mark of his depravity, a supernumerary nipple on his upper left chest.

  ARTEMIS EPHESIA

  Breasts bring us back to Linnaeus. In 1761, made famous by Systema naturae, Linnaeus published one of his lesser-known works, a synopsis of the Swedish animals called Fauna svecica. The name was revolutionary: it was the first time that the word ‘fauna’ – from the Roman name for Pan-the-God – had been used to describe a work of this sort; a direct counterpart to the ‘floras’ that were already proliferating. As a frontispiece to this work Linnaeus chose a curious emblem, a representation of the Greek goddess Artemis, or Diana, of Ephesus. We don’t know why he picked this particular emblem, but there are several possibilities.

  Artemis Ephesia was, in the inexplicably duplicitous way of Greek deities, goddess of both nature and cities. In her original incarnation as the object of a cult that flourished in Asia Minor from around the sixth century BC, her image was hung on city walls to protect them from evil, while being surrounded by icons of the country: garlands of vines and climbing animals such as lions, snakes, birds and harpies. Retrieved from the ruins of Ephesus, the eighteenth century made her into a symbol of wild-ness and of reason. The Jacobins even dedicated a Temple of Reason to her that once stood in Strasbourg, but is now gone. Perhaps this is why Linnaeus placed her at the front of his Fauna – as a symbol of the mastery of Reason over Nature, albeit a Swedish nature, in which, far from her Mediterranean home, Artemis stands among browsing reindeer.

  ARTEMIS EPHESIA IN SWEDEN. FRONTISPIECE OF LINNAEUS 1761 Fauna svecica.

  But perhaps she had another, more direct, meaning for Linnaeus as well. What is most striking about his Artemis are not the animals that surround her, but her four prominent breasts. In this she is a direct echo of the statues of her in antiquity, all of which are laden with a varying number of thoracic and abdominal protuberances. In the Renaissance these bumps were invariably interpreted as a case of extreme polymastia, but more sceptical modern scholars say they are more likely to have simply been strings of dates, bulls’ testicles, or perhaps just part of the cuirass in which the goddess was clad. Be that as it may, Linnaeus’ Artemis obviously has four fine breasts, and it seems quite possible that they are a direct allusion to one of his finest inventions, the Mammalia. For Linnaeus made the presence of mammary glands one of the defining features of what we are: members of that great class of creatures that embraces simultaneously the pygmy shrew and the blue whale.

  There is a third possible source of Linnaeus’ Artemis, one that brings us back to where we started – the way in which we differentiate ourselves from the rest of brute creation. When describing a species, Linnaeus did what taxonomists still do – he listed the things that distinguish it from all others. For all species, that is, but one: our own. When it came to Homo sapiens, instead of speaking of the number and kinds of teeth we have, the density of our hair, the distribution of our nipples, Linnaeus wrote only this: Nosce te ipsum. In a footnote he says that these are the words of Solon written in letters of gold upon the temple of Diana. Perhaps in choosing Artemis Ephesia as his icono-graphic symbol, Linnaeus is remembering and alluding to this account of the human species, the most concise possible: know thyself.

  That is where Linnaeus’ discussion of Homo sapiens ends, but for a few strangely exigent epigrams in which he instructs us in the meaning of the new identity that he has given us. ‘Know thyself,’ he says, created by God; blessed with minds with which to worship Him; as the most perfect and wonderful of machines; as masters of the animals; as the lords of creation – all sentiments that today ring with the poignancy of certainties long since gone. Yet it is his parting shot that is most telling, and that could be taken as epigrammatic of much of what I have written here:

  Know thyself, pathologically, what a fragile bubble you are, and exposed to a thousand calamities.

  If you understand these things, you are man, and a genus very distinct from all the others.

  IX

  THE SOBER LIFE

  [ON AGEING]

  HUNTINGTON DISEASE is one of the nastier neurodegenerative syndromes. It usually first appears as a mild psychosis and does not seem especially serious. But, as the disease progresses, the psychotic episodes increase in frequency and severity. Motor-coordination also deteriorates, a characteristic rigidity of gait and movement sets in and then, eventually, paralysis. In the disorder’s final phase, which can take up to ten or twenty years to appear, the patient becomes demented and experiences neural seizures, one of which is eventually fatal. The disease is caused by dominant mutations that disable a protein used in synaptic connections of the brain’s neurons. For reasons that are not fully understood, the mutant form of the protein initiates a molecular programme that gradually kills the neurons instead.

  LUIGI CORNARO (1464–1566). TINTORETTO.

  Huntington disease has several strange features. One is the way in which its symptoms become more severe from one generation to the next. This phenomenon, called ‘anticipation’, arises from a peculiarity of the Huntington gene itself and the mutations that cause the disease. The gene contains a region in which three nucleotides, CAG, are repeated over and over again. Most people have between eight and thirty-six of these repeats. Huntington disease mutations increase the number of repeats, so disordering the structure of the protein. Several mutations of this sort cripple the protein ever further over successive generations, increasing the severity of the disease.

  Another oddity of Huntington is its frequency. It afflicts about 1 in 10,000 Europeans. This is very high – most dominant mutations that kill have frequencies of about one in a million. But Huntington disease can persist in a family for generations. In 1872, George Huntington, a New York physician, described the disorder from families in Long Island, New York. Among their ancestors was one Jeffrey Ferris who emigrated from Leicester, England, in 1634. He almost certainly had the disease, as do many of his descendants today. In South Africa, about two hundred Huntington’s patients are descended from Elsje Cloetens, the daughter of a Dutchman who arrived with Jan van Riebeeck to found the Cape Colony in 1652. A large group of Huntington’s patients who live near Lake Maracaibo, Venezula, are the decendants of a German sailor who landed there in 1860.

  How can so lethal a disorder transcend the span of so many generations? In 1941 the brilliant and eccentric British geneticist J.B.S. Haldane proposed an answer. He pointed out that, unlike most genetic disorders, the symptoms of Huntington disease usually appear in middle age. By this time most people with the defective gene have had their children – each of whom will have had a 50 per cent chance of inheriting the defective gene. Unlike most lethal dominant mutations that kill in childhood and so are never transmitted to the following generation, the Huntington mutation hardly impairs the reproductive success of those who bear it. Middle age is almost invisible to natural selection.

  Few other disorders caused by a single mutation have such devastating effects so late in life. Yet the strangeness of Huntington disease is deceptive, for Haldane’s explanation of why it is so common also explains, with a little generalisation, why we, and most other animals, age. In this chapter I will argue that ageing is a genetic disorder, or rather, it is many genetic disorders, some of which afflict us all, others of which afflict only some of us. This point of view goes against the grain of most definitions of disease. Medical tradition distinguishes between ‘normal’ ageing, about which nothing much is done, and ‘age-related diseases’, such as arteriosclerosis, cancer and osteoporosis, that consume vast amounts of national health budgets. But this distinction is an illusion, a necessary medical fiction that allows physicians to ignore a disease that affects us all but which they are impotent to cure or even ameliorate. Properly understood, ageing is precisely what it seems: a grim and universal affliction.

  IMPOTENT SELECTION

  Ageing is the intrinsic decline of o
ur bodies. Its most obvious manifestation is the increased rate at which we die as we grow older. An eight-year-old child in a developed country has about a 1 in 5000 chance of not seeing her next birthday; for an eighty-year-old it is about 1 in 20. Of course, it is possible to be killed by causes quite unrelated to ageing – violence, contagious disease, accidents – but their collective toll is quite small. Were it not for ageing’s pervasive effects, 95 per cent of us would celebrate our centenaries; half of us would better the biblical Patriarchs by centuries and live for more than a thousand years. We could see in the fourth millennium AD.

  The evolutionary explanation for why we, and most other creatures, age rests upon two ideas, both implicit in Haldane’s explanation for the frequency of Huntington disease. The first is that the ill-effects of some mutations are felt only late in life. Most obviously a mutation might cause a slow-progressing disease. The Huntington mutation is just such a time-bomb. So is the SOST mutation that causes sclerosteosis in Afrikaaners; children are relatively unaffected but the excess bone growth kills in middle age. So are mutations in BRCA1, the familial breast-cancer gene whose ill-effects are usually felt only by women in their thirties and forties. And so is a variant of the APOE gene called ?-4 that predisposes elderly people to heart attacks and Alzheimer’s.